Ineffectiveness of High‐Dose Methotrexate for Prevention of CNS Relapse in DLBCL
abstract
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Access this abstract nowCentral nervous system (CNS) relapse affects 5% of diffuse large B cell lymphoma (DLBCL) patients and portends a poor prognosis. Prophylactic intravenous high-dose methotrexate (HD-MTX) is frequently employed to reduce this risk, but there is limited evidence supporting this practice. We conducted a multicenter retrospective study to determine the CNS relapse risk with HD-MTX in DLBCL patients aged 18-70 years treated in Alberta, Canada between 2012-2019. Provincial guidelines recommended HD-MTX for patients at high-risk of CNS relapse based upon CNS-IPI score, double-hit lymphoma, or testicular involvement. Among 906 patients with median follow-up 35.3 months (range 0.29-105.7), CNS relapse occurred in 1.9% with CNS-IPI 0-1, 4.9% with CNS-IPI 2-3, and 12.2% with CNS-IPI 4-6 (p<0.0001). HD-MTX was administered to 115/326 (35.3%) high-risk patients, of whom 96 (83.5%) had CNS-IPI score 4-6, 45 (39.1%) had double-hit lymphoma, and 4 (3.5%) had testicular lymphoma. The median number of HD-MTX doses was 2 (range 1-3). CNS relapse risk was similar with versus without HD-MTX (11.2% vs. 12.2%, p=0.82) and comparable to previous reports of high-risk patients who did not receive CNS prophylaxis (10-12%). In multivariate and propensity score analyses, HD-MTX demonstrated no association with CNS relapse, progression-free survival, or overall survival. This study did not demonstrate a benefit of prophylactic HD-MTX in this high-risk patient population. Further study is required to determine the optimal strategy to prevent CNS relapse in DLBCL. This article is protected by copyright. All rights reserved.
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Ineffectiveness of High-Dose Methotrexate for Prevention of CNS Relapse in Diffuse Large B Cell Lymphoma
Am. J. Hematol 2021 Apr 03;[EPub Ahead of Print], R Puckrin, H El Darsa, S Ghosh, A Peters, C Owen, D StewartFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Although retrospective, the results of that study are clear: adding high-dose IV methotrexate to the standard R-CHOP regimen does not prevent CNS relapse of DLBCL patients at high-risk for this dramatic event. These results will probably never be challenged by a prospective randomized trial. Thus, given unfavorable risk–benefit balance, this can no longer recommended as a routine. Whether or not this addition would benefit patients with subclinical CNS involvement as detected by cerebrospinal fluid analysis of tumor-specific cell-free DNA remains to be demonstrated.
To Be or Not to Be—CNS Prophylaxis of Diffuse B-Cell Lymphoma
Controversy exists for decades on the type and value of CNS prophylaxis for high-risk aggressive lymphoma. Here colleagues analyzed the adoption of CNS prophylaxis according to provincial guidelines of Alberta, Canada, and evaluated the outcome for patients with high-risk diffuse large B-cell lymphoma. Their guidelines since 2012 recommend for CNS prophylaxis to include high-dose methotrexate (>3 g/m2) in treatment regimens for high-risk lymphoma (here defined as CNS-IPI score 4–6, or double hit-lymphoma or testicular involvement); yet only 35% (115/326 high-risk lymphoma patients) received the guideline-suggested treatment. The risk for CNS relapse in this high-risk group was 12.2% (95% C,: 4.0–25.2), with no difference between patients who received HD-MTX versus no HD-MTX prophylaxis. Of note, however, the median number of administrations of HD-MTX was only two(!). The authors conclude that CNS prophylaxis with HD-MTX is futile.
This conclusion may be premature; two administrations of HD-MTX may not be sufficient to have a lasting effect on tumor control (for the systemic disease we are delivering six to eight cycles of a combination regimen!). Indirect evidence suggests that treatment intensification reduces CNS relapse rated. Patients undergoing consolidative auto-transplant have a CNS relapse rate of 6.0 (95% CI, 0.06–34.7) compared with patients without consolidation transplant (13.7%; 95% CI, 4.7–27.4). Of note, also are the large overlapping confidence intervals, indicating that the number of events is too few and the heterogeneity in outcomes too variable to allow for any statistical comparisons.
Over 31% of patients with CNS relapse received whole-brain radiotherapy as salvage therapy. Nevertheless, the median overall survival post-CNS relapse was only 6 months. This is a low bar to meet, and prospective trials with novel brain-penetrant agents should be investigated.
Still, there has been progress over the last decade. Current criteria allow us to accurately identify patients who are at high risk for CNS disease, albeit that CNS relapse is commonly also associated with systemic recurrence, and isolated CNS failure remains the exception. The CNS International Prognostic Index (CNS-IPI) identified six independent risk factors; namely, renal or adrenal involvement, age >60 years, elevated LDH, ECOG performance status ≥2, stage III/IV lymphoma, and extranodal involvement beyond a single site; four or more of these criteria constitute high-risk disease. Furthermore, testicular involvement and double-hit lymphoma are considered high-risk for CNS relapse. In the Canadian report, the incidence of CNS recurrence was 11.8% (95% CI, 4.1–23.9) compared with 3.0% (95% CI, 0.2–14.2) for non–high-risk disease.
This well-written report will likely neither change our practice, nor the, in general, lukewarm attitude towards CNS prophylaxis. To tease out a benefit of a certain treatment approach when the incidence of the event is rare (in the Canadian report, in 59% of CNS relapses, there was also systemic disease recurrence) will be almost impossible. Furthermore, we know that dose intensity and combination chemotherapy play an important role in the treatment of aggressive lymphoma; yet, many of the agents do not cross the blood–brain barrier sufficiently, and two administrations of moderate doses of methotrexate cannot make up for the insufficient drug concentrations across the blood–brain barrier. Future strategies will need to address combination regimens of drugs with both systemic activity and that have adequate penetration into the CNS. Recent encouraging reports of IMiDs and Bruton kinase inhibitors as well as incorporation of sufficient cycles and doses of HD-MTX may be a way forward.